Marine natural product des-O-methyllasiodiplodin effectively lowers the blood glucose level in db/db mice via ameliorating inflammation

Aim： des-O-methyllasiodiplodin （DML） from Cerbera manghas has shown antagonistic activity against mineralocorticoid receptor （MR）. Considering the involvement of MR in the insulin tolerance, we attempted to investigate the potential of DML in the treatment of type 2 diabetes mellitus （T2DM）. Methods： Surface plasmon resonance （SPR） technology and reporter gene-based assays were used to study protein-small molecule interactions. HepG2 and 3T3-L1 cells were treated with H202 （0.2 mmol/L） or aldosterone （10 nmol/L） for 24 h. The expression of MR in the cells was downregulated with siRNA. The anti-inflammatory effect of the compound was evaluated, respectively, db/db mice were administered DML （30 mg.kg-1〈1-1） for 4 weeks. Serum biochemical parameters and insulin sensitivity were examined. The expression levels of pro-inflammatory cytokines （MCP-1, TNF-a, and IL-6） and ROS-related genes （NADPH p47 subunit and transcrip- tional factor PU.1） in adipose tissues and livers were analyzed using real-time RT-PCR. Results： In HepG2 and 3T3-L1 cells, both H202 and aldosterone markedly stimulates the expression of MCP-1, TNFα, IL-6, p47, and PU.1 genes. Co-treatment with DML （10 pmol/L） significantly reduced the H2O2- or aldosterone-induced expression of these genes. SPR-based assay confirmed the antagonistic activity of DML against the interaction between SRC-1 and MR-LBD. Furthermore, DML decreased aldosterone-induced MR transcriptional activity in a dose-dependent manner. Downregulation of MR with siRNA in the cells prevented or significantly attenuated aldosterone-stimulated expression of these genes, whereas DML did no longer affect the expres- sion of these genes except that of IL-6. Oral administration of DML effectively reduced the levels of blood glucose and glycosylated hemoglobin （HbAlc） in db/db mice. The treatment also rectified the expression of pro-inflammatory factor and ROS-related genes in db/db mice. Conclusion： DML effectively lowers the blood glucose level in db/db mice possibly via ameliorating the expression of obesity-related pro-inflammatory cytokines, highlighting the potential of the marine natural product as a drug lead for the treatment of metabolic disor- ders.